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DNA methylation fingerprint of a KDM5C loss-of-function mutation in patients with intellectual disability

ABSTRACT: DNA methylation fingerprint of a KDM5C loss-of-function mutation in patients with intellectual disability

PROVIDER: PRJNA427263 | ENA |

REPOSITORIES: ENA

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DNA methylation fingerprint of a KDM5C loss-of-function mutation in patients with intellectual disability

Project description:Characterization of methylation changes related do KDM5C c.807delC (p.V271X) Mutations in KDM5C (lysine (K)-specific demethylase 5C) were associated to up to 3% of the X-linked ID cases. Males carrying KDM5C mutations present reduced activity of the KDM5C protein, increasing H3K4 tri-methylation, which ultimately leads to up-regulation of KDM5C target genes. Whole-exome sequencingi n one of three brothers with intellectual disability followed by confirmation by Sanger sequencing in the family identified a frameshift mutation in the KDM5C exon 7 that devoid of the JmjC catalytic domain from the protein. Two other brothers also presenting intellectual disability as well as in their clinically normal mother, who had completely skewed X-inactivation also had the mutation. An empirical Bayesian analysis of methylation levels between cases and controls identified 399 differentially methylated positions, 288 hypomethylated and 111 hypermethylated.Among the genes associated with the hypomethylated CpGs were FBXL5 and CACYBP, both involved in the ubiquitination pathway.

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Project description:Intellectual disability (ID) is a clinically important disease and a most prevalent neurodevelopmental disorder. The etiology and pathogenesis of ID are poorly recognized. Exome sequencing revealed a homozygous missense mutation in the POLR3B gene in a consanguineous family with three Intellectual disability with craniofacal anomalies patients. POLR3B gene encoding the second largest subunit of RNA polymerase III. To explore how genetic variants alter cell expression in ID patients, RNA sequencing on blood samples was performed and to obtain insights into the biological pathways influenced by POLR3B mutation, we applied our RNA-Seq data to several gene ontology programs such as ToppGene, Enrichr, KEGG. We detected a significant decrease expression of several spliceosomal RNAs, ribosomal proteins and transcription factors in our ID patients. We hypothesize that POLR3B mutation dysregulates the expression of some important transcription factors, ribosomal and spliceosomal genes and impairments in protein synthesis and splicing mediated in part by transcription factors such as FOXC2, GATA1, .. contribute to impaired neuronal function and concurrence of intellectual disability and craniofacial anomalies in our patients. Our study highlights the emerging role of spliceosome and ribosomal proteins in intellectual disability.

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KDM5C safeguards the appropriate timing of early neurodevelopment

Project description:We generated human induced pluripotent cells from intellectual disability patients carrying the c.2T>C mutation in KDM5C (Called “Mutant”). We generated a paired, isogenic human iPS cell line (called “Corrected”) using CRISPR/Cas9 and PiggyBac gene-editing technologies and conducted neuronal differentiation based on “Yichen Shi et al. Nat. Protoc. 7, 1836–1846 (2012)” to define differences in gene expression between the Mutant and Corrected during neurodevelopment.

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NONO mutations cause syndromic intellectual disability and inhibitory synaptic defects

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Sexually Dimorphic Alterations in the Transcriptome and Behavior with Loss of Histone Demethylase KDM5C

Project description:Chromatin dysregulation has emerged as a major hallmark of neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorders (ASD). The prevalence of ID and ASD is higher in males compared to females, with un-known mechanisms. Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type (MRXSCJ), is caused by loss-of-function mutations of lysine de-methylase 5C (KDM5C), a histone H3K4 demethylase gene. KDM5C escapes X-inactivation, thereby presenting at a higher level in females. Initially, MRXSCJ was exclusively reported in males, while it is increasingly evident that females with heterozygous KDM5C mutations can show cognitive deficits. The mouse model of MRXSCJ, male Kdm5c-hemizygous knockout animals, recapitulates key features of human male patients. However, the behavioral and molecular traits of Kdm5c-heterozygous female mice remain incompletely characterized. Here, we re-port that gene expression and behavioral abnormalities are readily detectable in Kdm5c-heterozygous female mice, demonstrating the requirement for a higher KDM5C dose in females. Furthermore, we found both shared and sex-specific con-sequences of a reduced KDM5C dose in social behavior, gene expression, and ge-netic interaction with the counteracting enzyme KMT2A. These observations pro-vide an essential insight into the sex-biased manifestation of neurodevelopmental disorders and sex chromosome evolution.

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Project description:10 patients with Intellectual Disability diagnosed with a clinically relevant copy number change, selected to assess the dection performance of alternative platforms.

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